Screening studies suggest that the prevalence of moderate to severe obstructive sleep apnea (OSA) in persons with tetraplegia ranges from 22% to 36%, thus greatly exceeding prevalence estimates of 9.1% in men and 4% in women encountered in the general population. Recent evidence indicates that untreated OSA carries increased risk for the development of hypertension, myocardial infarction, and stroke. The prevailing mechanism felt to underlie the association between OSA and adverse cardiovascular sequellae is heightened sympathetic nervous system activity stemming from repetitive apneic events, although falls in cardiac output that accompany large negative intrathoracic pressure swings, and repetitive hypoxia/reoxygenation associated with oxidative stress and endothelial dysfunction have also been implicated. In contrast to neurologically intact persons, individuals with tetraplegia represent a model of sympathetic denervation characterized by relative bradycardia and low resting blood pressure. It is unknown whether OSA confers increased cardiovascular disease risk in these individuals, although the prevalence of cardiovascular disease and attributable mortality appear to be greater than that encountered in the general population. We suspect that obstructive sleep apnea complicating tetraplegia imposes significant hemodynamic stress due to falls in cardiac output during apneic events not arrested by catecholamine-induced chronotropic, inotropic, and vasopressor effects. Muscle paralysis and blunted hypercapnic ventilatory responsiveness in persons with tetraplegia, which are also normal rapid eye movement (REM) sleep phenomena, could predispose to greater apnea severity and potentiate falls in cardiac output similar to that observed during REM sleep in able-bodied persons, but will likely occur regardless of sleep stage. We also anticipate that falls in cardiac output and renal hypoperfusion will lead to activation of the renin-angiotensin system, the chronic up- regulation of which has been associated with increased cardiovascular mortality. The purpose of this pilot investigation is therefore to determine in a human model of respiratory muscle paralysis and impaired sympathetic cardiovascular control whether persons with tetraplegia diagnosed with OSA manifest greater decreases in cardiac output during apneic events than that witnessed in neurologically intact individuals with OSA. In the context of the acute hemodynamic changes associated with OSA in these two groups, and in comparison to a third group of subjects with tetraplegia without OSA, we will also examine differences in urinary markers of catecholamine release (vanillyl mandelic acid, metanephrines and normetanephrine), and in plasma levels of atrial natriuretic factor, a marker of atrial stretch. A secondary objective of this pilot investigation will be to investigate whether nocturnal plasma renin and serum aldosterone concentrations differ among individuals with tetraplegia and OSA compared to their counterparts without OSA. An exploratory aim will be to determine if hypoxemia stemming from repetitive apneas leads to elevation in markers of vascular inflammation, specifically high sensitivity C-reactive protein and interleukin-6, in individuals with OSA compared to those without OSA. PUBLIC HEALTH RELEVANCE: Relevance of the Proposed Work to the VA Patient Care Mission Fostering a better understanding of the common medical conditions that beset veterans with SCI and how best to treat them, with the ultimate goal of improving quality of life for these individuals is highly relevant to the VA Patient Care Mission. Investigation of the acute cardiovascular events associated with repetitive obstructive apneas during sleep in persons with tetraplegia is a necessary first step toward gaining an understanding of the hemodynamic and potentially deleterious consequences of OSA in this population. Subsequent investigations based upon preliminary data from this pilot investigation, forming the basis for a full Merit Review, would be geared toward expanding upon initial observations and evaluating treatment effects, of which little is known [10, 35, 79, 79].